title: Metabolomic profile of response to supplementation with β-carotene in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study.
abstract: BACKGROUND
  Two chemoprevention trials found that supplementation with β-carotene increased the risk of lung cancer and overall mortality. The biologic basis of these findings remains poorly understood.
  
  
  OBJECTIVE
  The objective was to compare the on-study change in metabolomic profiles of men randomly assigned to receive or not receive β-carotene supplements in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study.
  
  
  METHODS
  The ATBC Study was a randomized, double-blind, placebo-controlled, primary cancer prevention trial; participants were Finnish male smokers assigned to 1 of 4 intervention groups: 1) α-tocopherol, 2) β-carotene, 3) both, or 4) placebo. Fifty participants with both baseline and follow-up fasting serum samples were randomly selected from each of these groups. Metabolomic profiling was conducted by mass spectrometry. The association between change in each metabolite over time and trial assignment (β-carotene or no β-carotene) was estimated by linear regression.
  
  
  RESULTS
  We measured 489 metabolites, and 17 changed significantly (P < 0.05) in response to β-carotene supplementation. More of these 17 metabolites were of xenobiotic origin than would be expected by chance (9 of 60, or 15%; P = 0.00004). We also found a suggestive association with 1,5-anhydroglucitol-a marker of glycemic control (β = -0.379, P = 0.0071).
  
  
  CONCLUSIONS
  Male smokers supplemented with β-carotene developed metabolomic profiles consistent with the induction of cytochrome P450 enzymes, the primary metabolizers of xenobiotics in humans. These findings may shed light on the increased mortality associated with β-carotene supplementation in the ATBC Study and suggest the need to explore potential interactions between medication use and dietary supplements, particularly among smokers. This trial was registered at clinicaltrials.gov as NCT00342992.
authors.affiliation: Nutritional Epidemiology Branch and the Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Department of Health and Human Services, Bethesda, MD, USA.
authors.forename: Alison M
authors.initials: AM
authors.lastname: Mondul
authors.forename: Joshua N
authors.initials: JN
authors.lastname: Sampson
authors.forename: Steven C
authors.initials: SC
authors.lastname: Moore
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Weinstein
authors.forename: Anne M
authors.initials: AM
authors.lastname: Evans
authors.forename: Edward D
authors.initials: ED
authors.lastname: Karoly
authors.forename: Jarmo
authors.initials: J
authors.lastname: Virtamo
authors.forename: Demetrius
authors.initials: D
authors.lastname: Albanes
mesh_terms: D000368:Aged; D001786:Blood Glucose / Q000032:analysis; D002853:Chromatography, Liquid; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics / Q000378:metabolism; D003847:Deoxyglucose / Q000008:administration & dosage; D019587:Dietary Supplements; D004311:Double-Blind Method; D005215:Fasting; D005387:Finland; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D055442:Metabolome; D008875:Middle Aged; D012307:Risk Factors; D012907:Smoking; D053719:Tandem Mass Spectrometry; D024502:alpha-Tocopherol / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D019207:beta Carotene / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood
chemical_list: D001786:Blood Glucose; D019207:beta Carotene; C006584:1,5-anhydroglucitol; D003847:Deoxyglucose; D019392:Cytochrome P-450 CYP2E1; C504573:CYP1A2 protein, human; D019388:Cytochrome P-450 CYP1A2; D024502:alpha-Tocopherol